Pyrazolo[1,5-a]pyrimidine derivatives

ABSTRACT

The invention provides pyrazolo[1,5-a]pyrimidine derivatives which are useful as potent analgesics and represented by the formula ##STR1## wherein R 1  is lower alkenyl, hydroxy(lower)alkyl, (lower)alkylthio(lower)alkyl, (lower)alkanoyloxy(lower)alkyl, (lower)alkoxy(lower)alkyl, furyl or thienyl, R 2  is pyridyl, 1-oxide-pyridyl, lower alkyl-substituted pyrazinyl, lower alkyl-substituted pyrimidinyl, or phenyl which may have 1 to 3 substituents selected from the group consisting of lower alkyl, lower alkoxy and halogen, R 3  is hydrogen or halogen, and A is a single bond or lower alkylene.

This application is a 371 of PCT/JP96/00955 filed Apr. 5, 1996.

TECHNICAL FIELD

The present invention relates to novel pyrazolo[1,5-a]pyrimidinederivatives.

PRIOR ART

The pyrazolo[1,5-a]pyrimidine derivatives of the invention are novelcompounds which have never been published in the literature.

DISCLOSURE OF THE INVENTION

An object of this invention is to provide compounds useful as medicine.The use of the compounds as medicine will be described hereinafter.

The present invention provides novel pyrazolo[1,5-a]pyrimidinederivatives represented by the following formula (1) ##STR2## wherein R¹is lower alkyl, lower alkenyl, hydroxy(lower)alkyl,(lower)alkanoyloxy(lower)alkyl, (lower)alkoxy(lower)alkyl,(lower)alkylthio(lower)alkyl, furyl or thienyl, R² is pyridyl,1-oxide-pyridyl, lower alkyl-substituted pyrazinyl, loweralkyl-substituted pyrimidinyl, or phenyl which may have 1 to 3substituents selected from the group consisting of lower alkyl, loweralkoxy and halogen, R³ is hydrogen or halogen, and A is a single bond orlower alkylene; with the proviso that when R¹ is lower alkyl, R² islower alkyl-substituted pyrazinyl or lower alkyl-substitutedpyrimidinyl.

Examples of the groups in the compounds represented by the formula (1)are as follows.

The lower alkyl group includes straight- or branched-chain lower alkylgroups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tert-butyl, pentyl, hexyl and the like.

The lower alkenyl group includes vinyl, allyl, isopropenyl, 1-butenyl,2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl and the like.

The hydroxy(lower)alkyl group includes hydroxymethyl, 1-hydroxyethyl,2-hydroxyethyl,3-hydroxy-propyl, 3-hydroxybutyl, 4-hydroxybutyl,5-hydroxypentyl, 6-hydroxyhexyl and the like.

The (lower)alkanoyloxy(lower)alkyl group includes acetoxymethyl,propionyloxymethyl, butyryloxymethyl, valeryloxymethyl,pivaloyloxymethyl, hexanoyloxymethyl, heptanoyloxymethyl,2-acetoxyethyl, 3-acetoxypropyl, 3-acetoxybutyl, 4-acetoxybutyl,5-acetoxypentyl, 6-acetoxyhexyl and the like.

The (lower)alkoxy(lower)alkyl group includes methoxymethyl,ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl,pentyloxymethyl, hexyloxymethyl, 2-methoxyethyl, 2-ethoxyethyl,3-methoxypropyl, 3-methoxybutyl, 4-methoxybutyl, 5-methoxypentyl,6-methoxyhexyl and the like.

The furyl group includes 2-furyl and 3-furyl.

The thienyl group includes 2-thienyl and 3-thienyl.

The pyridyl group includes 2-pyridyl, 3-pyridyl and 4-pyridyl.

The 1-oxide-pyridyl group includes 1-oxide-2-pyridyl, 1-oxide-3-pyridyland 1-oxide-4-pyridyl.

The halogen atom includes fluorine, chlorine, bromine and iodine.

The lower alkoxy group includes methoxy, ethoxy, propoxy, isopropoxy,butoxy, pentyloxy, hexyloxy and the like.

The (lower)alkylthio(lower)alkyl group includes methylthiomethyl,ethylthiomethyl, propylthiomethyl, butylthiomethyl, pentylthiomethyl,hexylthiomethyl, 2-methylthioethyl, 2-ethylthioethyl,3-methylthiopropyl, 3-methylthiobutyl, 4-methylthiobutyl,5-methylthiopentyl, 6-methylthiohexyl and the like.

The lower alkyl-substituted pyrimidinyl group includes4-methyl-2-pyrimidinyl, 5-methyl-2-pyrimidinyl,4,6-dimethyl-2-pyrimidinyl, 4-ethyl-2-pyrimidinyl,5-ethyl-2-pyrimidinyl, 4,6-diethyl-2-pyrimidinyl,4-propyl-2-pyrimidinyl, 5-propyl-2-pyrimidinyl,4,6-dipropyl-2-pyrimidinyl, 4-butyl-2-pyrimidinyl,5-butyl-2-pyrimidinyl, 4,6-dibutyl-2-pyrimidinyl,4-pentyl-2-pyrimidinyl, 5-pentyl-2-pyrimidinyl,4,6-dipentyl-2-pyrimidinyl, 4-hexyl-2-pyrimidinyl,5-hexyl-2-pyrimidinyl, 4,6-dihexyl-2-pyrimidinyl and the like.

The lower alkyl-substituted pyrazinyl group includes2-methyl-5-pyrazinyl, 2-methyl-3-pyrazinyl, 2-methyl-6-pyrazinyl,2-ethyl-5-pyrazinyl, 2-propyl-5-pyrazinyl, 2-butyl-5-pyrazinyl,2-pentyl-5-pyrazinyl, 2-hexyl-5-pyrazinyl and the like.

The lower alkylene group includes methylene, ethylene, trimethylene,tetramethylene, pentamethylene, hexamethylene and the like.

The phenyl group which may have 1 to 3 substituents selected from thegroup consisting of lower alkyl, lower alkoxy and halogen includesphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-ethylphenyl,4-propylphenyl, 4-butylphenyl, 4-t-butylphenyl, 4-pentylphenyl,4-hexylphenyl, 2,3-dimethylphenyl, 2,4-dimethylphenyl,2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4-dimethylphenyl,3,5-dimethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl,4-ethoxyphenyl, 4-propoxyphenyl, 4-butoxyphenyl, 4-pentyloxyphenyl,4-hexyloxyphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl,2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4-dimethoxyphenyl,3,5-dimethoxyphenyl, 2,3,4-trimethoxyphenyl, 2,3,5-trimethoxyphenyl,2,3,6-trimethoxyphenyl, 2,4,5-trimethoxyphenyl, 2,4,6-trimethoxyphenyl,3,4,5-trimethoxyphenyl, 3,4,5-triethoxyphenyl, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl,4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl,4-iodophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl,3-methoxy-4-methylphenyl, 3-chloro-4-methylphenyl,3-chloro-4-methoxyphenyl and the like.

The pyrazolo[1,5-a]pyrimidine derivatives of formula (1) according tothe invention have potent analgesic effects and are useful as analgesicsto relieve pains such as postoperative pain, migraine, gout, cancerpain, chronic pain and neuropathic pain. Moreover, the derivatives ofthe invention are free of side effects typical of conventionalanalgesics, do not cause hallucination or derangement and are notaddictive.

The following pyrazolo[1,5-a]pyrimidine derivatives of the invention aresuitable for use as analgesics: compounds of formula (1) wherein R¹ islower alkyl and R² is lower alkyl-substituted pyrazinyl or loweralkyl-substituted pyrimidinyl; those wherein R¹ is furyl and R² isphenyl which may have 1 to 3 substituents selected from the groupconsisting of lower alkyl, lower alkoxy and halogen; and those whereinR² is pyridyl or 1-oxide-pyridyl and A is lower alkylene.

Of these suitable pyrazolo[1,5-a]pyrimidine derivatives, preferred arecompounds of formula (1) wherein R¹ is lower alkenyl, R² is pyridyl or1-oxide-pyridyl, R³ is hydrogen and A is lower alkylene and thosewherein R¹ is furyl, R² is phenyl having 1-3 lower alkoxy groups assubstituents, R³ is hydrogen and A is lower alkylene. The mostpreferable are those wherein R¹ is 3-butenyl or 2-furyl and A ismethylene.

The most preferable pyrazolo[1,5-a]pyrimidine derivatives of theinvention include5-(3-butenyl)-7-(4-pyridylmethoxy)pyrazolo[1,5-a]pyrimidine,4-[5-(3-butenyl)pyrazolo[1,5-a]pyrimidin-7-yl-oxymethyl]pyridine-1-oxideand 5-(2-furyl)-7-(3,4,5-trimethoxybenzyloxy)-pyrazolo[1,5-a]pyrimidine.

The derivatives of formula (1) according to the invention can beproduced by various processes. Some exemplary processes areschematically shown below. ##STR3## wherein A is as defined above,R^(1a) is lower alkyl, lower alkenyl, (lower)alkoxy(lower)alkyl,(lower)alkylthio-(lower)alkyl, furyl or thienyl, R^(2a) is pyridyl,lower alkyl-substituted pyrazinyl, lower alkyl-substituted pyrimidinyl,or phenyl which may have 1 to 3 substituents selected from the groupconsisting of lower alkyl, lower alkoxy and halogen, X is halogen and Zis lower alkyl; with the proviso that when R^(1a) is lower alkyl, R^(2a)is lower alkyl-substituted pyrazinyl or lower alkyl-substitutedpyrimidinyl.

The condensation reaction of the compound (2) and 3-aminopyrazole (3) inReaction Scheme-1 is carried out in a suitable inert solvent at atemperature ranging from room temperature to the boiling point of thesolvent. Examples of useful inert solvents are acetic acid, ethanol,benzene, toluene, xylene, tetrahydrofuran (THF) and the like. Thecompound (2) and 3-aminopyrazole (3) are preferably used in anapproximately equimolar proportion. The reaction is carried out forabout 2-5 hours to provide the desired compound (4).

The subsequent halogenation reaction of the compound (4) is carried outin the presence of a suitable deacidification agent such asN,N-dimethylaniline, N,N-diethylaniline, triethylamine or the like,using a halogenating agent such as phosphorus oxychloride, phosphorusoxybromide or the like. Since the halogenating agents also function assolvents, there is no need to use other solvents in the reaction but aninert solvent such as benzene, toluene, xylene or the like may beoptionally used. The deacidification agent is preferably used in anamount of about 1-10 times by weight of the compound (4). The reactionis carried out at a temperature from room temperature to about 150° C.and completed in about 0.5-12 hours.

The halide (5) obtained by the reaction is reacted with an alcoholderivative (6), giving a compound (1a) of the invention. The reaction isusually carried out in a suitable solvent in the presence of adeacidification agent.

Examples of useful deacidification agents are inorganic bases, forexample, hydroxides of alkali metals such as sodium hydroxide andpotassium hydroxide; bicarbonates such as sodium hydrogencarbonate; andcarbonates such as potassium carbonate; and tertiary amines such astriethylamine, N,N-diethylaniline, N-methylmorpholine, pyridine and4-dimethylaminopyridine.

Examples of useful solvents are inert solvents, for example, loweralcohols such as methanol and ethanol; chain or cyclic ethers such astetrahydrofuran (THF) and 1,4-dioxane; and N,N-dimethylformamide (DMF)and dimethyl sulfoxide (DMSO). In the case of using an inorganic base asa deacidification agent, a mixed solvent of an inert solvent and wateris preferably used. Examples of useful solvents further include aromatichydrocarbon such as benzene, toluene, xylene and the like.

There is no limitation on the amounts of the alcohol derivative (6) anddeacidification agent relative to the halide (5) in the above reaction.They are preferably used in an approximately equimolar to excessivemolar amount respectively. The reaction proceeds under any of thefollowing conditions; cooling, room temperature and heating. Thereaction is usually carried out at a temperature ranging from 0° C. toreflux temperature of the solvent and completed in about 0.5-15 hours.##STR4## wherein R^(2a), A, X and Z are as defined above, Ψ representslower alkyl having protected carbonyl, Φ represents lower alkyl havingcarbonyl, R^(1b) represents hydroxy(lower)alkyl and R^(1c) represents(lower)alkanoyloxy(lower)alkyl.

In Reaction Scheme-2, the condensation reaction of the compound (7) and3-aminopyrazole derivative (3) can be carried out in a similar manner asin the reaction of the compound (2) and 3-aminopyrazole derivative (3)in Reaction Scheme-1.

Referring to "lower alkyl having protected carbonyl" represented by Ψ inthe compound (7), examples are lower alkyl groups having as protectedcarbonyl the residue of di(lower)alkylacetal such as dimethylacetal,methylethylacetal, diethylacetal, dipropylacetal, dibutylacetal,dipentylacetal, dihexylacetal and the like and lower alkyl groups havingas protected carbonyl the residue of cyclic acetal such asethyleneacetal, trimethyleneacetal, tetramethyleneacetal and the like.

The subsequent hydrolysis reaction of the compound (8) according toReaction Scheme-2 can be carried out using an organic acid such asacetic acid, propionic acid, p-toluenesulfonic acid or the like. Ofthese organic acids, carboxylic acids such as acetic acid and propionicacid can also function as solvents. When such a carboxylic acid is used,no other solvents are necessary. Even in such a case, other suitableinert solvents such as benzene, toluene, xylene or the like may beoptionally used. The reaction is carried out at a temperature from roomtemperature to about reflux temperature of the solvent for about 10-80hours to provide the compound (9).

The "lower alkyl having carbonyl" represented by Φ in the compound (9)includes those obtained by elimination of the protective group from thecorresponding "lower alkyl having protected carbonyl" represented by Ψ.Examples are formyl, formylmethyl, acetyl, 2-formylethyl, 2-oxopropyl,propionyl, 3-formylpropyl, 3-oxobutyl, 2-oxobutyl, butyryl,4-formylbutyl, 4-oxopentyl, 3-oxopentyl, 2-oxopentyl, valeryl,5-formylpentyl, 5-oxohexyl, 4-oxohexyl, 3-oxohexyl, 2-oxohexyl, hexanoyland the like.

The subsequent reduction reaction of the compound (9) is carried outusing a suitable reducing agent in an inert solvent. Examples ofreducing agents are borohydride compounds such as sodium borohydride,potassium borohydride, lithium borohydride, sodium cyanoborohydride,sodium triethylborohydride and the like; and lithium aluminum hydridecompounds such as lithium aluminum hydride, lithiumtributoxyaluminohydride and the like.

When a borohydride compound is used as a reducing agent, suitable inertsolvents are alcohols such as methanol, ethanol or mixed solvents of thealcohol and another solvent such as dichloromethane, diethyl ether, etc.When a lithium aluminum hydride compound is used as a reducing agent,suitable solvents are diethyl ether, THF and like ethers. The reducingagent is preferably used in at least approximately equimolar proportionrelative to the compound (9). The reaction is carried out at atemperature ranging from approximately 0° C. to room temperature forabout 0.5-3 hours.

The compound (10) thus obtained is alkanoylated using an alkanoylatingagent in the absence of solvents or in an inert solvent such aspyridine, lutidine, DMF or DMA. Suitable alkanoylating agents includeacetic anhydride, propionic anhydride, butyric anhydride, valericanhydride, hexanoic anhydride, heptanoic anhydride and like acidanhydrides. The alkanoylating agent is usually used in an amount of 1-10equivalents relative to the compound (10). In order not to alkanoylatethe hydroxyl group at the 7-position of the compound (10), the reactionconditions are preferably selected from a temperature range ofapproximately 0° C. to room temperature and a time range of about 0.5 to2 hours.

Halogenation reaction of the compound (11) thus obtained can be carriedout in a similar manner as in the reaction of the compound (4) shown inReaction Scheme-1.

Lastly, the compound (12) thus obtained is reacted with an alcoholderivative (6) to provide the desired compounds (1b) and (1c) of theinvention. This reaction can be carried out in a similar manner as inthe reaction using an alcohol derivative (6) in Reaction Scheme-1. Whenabout 1 equivalent of a deacidification agent is used in the reaction,the compound (1b) is formed as a main product. With use of adeacidification agent in an excessive amount, the compound (1c) isobtained as a main product. ##STR5## wherein R^(1d) is lower alkenyl,(lower)alkanoyloxy(lower)alkyl, (lower)alkoxy(lower)alkyl, furyl orthienyl, and R³ and A are as defined above.

As shown in Reaction Scheme-3, the compound (1d) is oxidated to give acompound (1e). The oxidation can be carried out in an inert solvent suchas methanol, ethanol, t-butanol, dichloromethane, chloroform, aceticacid or methanol-water and in the presence of a suitable oxidizing agentsuch as m-chloroperbenzoic acid, peracetic acid, aqueous hydrogenperoxide solution, or t-butylhydroperoxide. The oxidizing agent isusually used in an equimolar to slightly excessive amount relative tothe compound (1d). The reaction is usually carried out at a temperatureranging from approximately 0° C. to room temperature for about 0.5-10hours. ##STR6## wherein R¹, R² and A are as defined above and R^(3a) ishalogen.

The halogenation reaction of the compound (1f) in Reaction Scheme-4 canbe carried out using a halogenating agent such as N-bromosuccinimide(NBS), N-chlorosuccinimide (NCS) or bromine in an inert solvent such asdimethoxyethane, dimethoxyethane-water, benzene, carbon tetrachloride orthe like. The halogenating agent is usually used in an amount of 1equivalent to a slightly excessive amount relative to the compound (1f).The reaction can be carried out at a temperature ranging fromapproximately 0° C. to room temperature for about 0.5-5 hours. ##STR7##wherein R², R³ and A are as defined above and Q is a single bond or C₁₋₄alkylene.

The conversion reaction of compound (1h) into compound (1i) shown inReaction Scheme-5 is carried out by hydroboration (oxidation) of thecompound (1h). More specifically, the compound (1h) is reacted with 1-3equivalents of a borohydride compound, such as diborane, borane-THFcomplex, borane-dimethyl amine complex, borane-methyl sulfide complex,9-BBN (9-borabicyclo-[3,3,1]nonane) or the like in an inert solvent suchas THF or diethyl ether at a temperature ranging from approximately -50°C. to room temperature for about 1 to 10 hours, and then the reactionmixture is treated with an aqueous alkali solution such as aqueous NaOHsolution or aqueous KOH solution and an excess of aqueous hydrogenperoxide solution at a temperature ranging from approximately -50° C. toroom temperature for about 0.5 to 5 hours.

Some compounds of the invention can be converted into pharmaceuticallyacceptable acid addition salts, which are also included in the scope ofthe invention. Examples of useful acids to form such salts arehydrochloric acid, hydrobromic acid, sulfuric acid and like inorganicacids; and oxalic acid, fumaric acid, maleic acid, tartaric acid, citricacid and like organic acids. These acid addition salts can be formed byconventional methods.

The desired compound in each of the above processes can be easilyisolated by conventional separation and purification means. Usefulisolation procedures include various conventional processes such asadsorption chromatography, preparative thin-layer chromatography,recrystallization, solvent extraction and the like.

Some compounds of formula (1) according to the invention may exist asoptical isomers having a carbon atom as asymmetric center. The inventioncovers all the optical isomers (racemic derivatives, R-derivatives andS-derivatives). Also, some compounds of formula (1) according to theinvention may exist as cis- or trans-isomers. The invention also coversthese isomers.

The pharmaceutical compositions of the invention can be made intogeneral dosage forms of pharmaceutical compositions using suitablepharmaceutically acceptable carrier(s).

Examples of useful pharmaceutically acceptable carriers are conventionaldiluents or excipients such as fillers, volume builders, binders,humectants, disintegrators, surfactants, lubricants and the like. Thesecarriers are selectively used according to the desired unit dosage form.

The unit dosage form for the pharmaceutical compositions of theinvention can be selected from a broad variety of forms according to theintended medical treatment. Typical examples are tablets, pills,powders, solutions, suspensions, emulsions, granules, capsules,suppositories, injections (solutions, suspensions, etc.), ointments andthe like.

The tablets can be molded using as pharmaceutically acceptable carriersexcipients such as lactose, sucrose, sodium chloride, glucose, urea,starch, calcium carbonate, kaolin, crystalline cellulose, silicic acidand potassium phosphate; binders such as water, ethanol, propanol,simple syrup, glucose syrup, starch solution, gelatin solution,carboxymethyl cellulose, hydroxypropyl cellulose, methyl cellulose andpolyvinyl pyrrolidone; disintegrators such as sodium carboxymethylcellulose, calcium carboxymethyl cellulose, low-substitutedhydroxypropyl cellulose, dry starch, sodium alginate, agar powder,laminaran powder, sodium hydrogen-carbonate and calcium carbonate;surfactants such as polyoxyethylene sorbitan fatty acid esters, sodiumlauryl sulfate and stearyl monoglyceride; disintegration inhibitors suchas sucrose, stearin, cacao butter and hydrogenated oil; absorptionpromoters such as quaternary ammonium base and sodium lauryl sulfate;humectants such as glycerin and starch; adsorbents such as starch,lactose, kaolin, bentonite and colloidal silicic acid; and lubricantssuch as purified talc, stearic acid salt, boric acid powder andpolyethylene glycol.

Furthermore, the tablets may be optionally coated to providesugar-coated tablets, gelatin-coated tablets, enteric tablets,film-coated tablets, etc. or be processed into double-layer ormultiple-layer tablets.

The pills can be molded using as pharmaceutically acceptable carriersexcipients such as glucose, lactose, starch, cacao butter, hydrogenatedvegetable oil, kaolin and talc; binders such as gum arabic powder,tragacanth powder, gelatin and ethanol; and disintegrators such aslaminaran and agar.

The suppositories can be molded using as pharmaceutically acceptablecarriers polyethylene glycol, cacao butter, higher alcohols or theiresters, gelatin, semisynthetic glycerides and the like.

The capsules are usually manufactured by mixing an active compound ofthe invention with pharmaceutically acceptable carriers as mentionedabove and filling the mixture into hard gelatin capsule shells, softcapsule shells, etc. according to conventional methods.

The injections in the form of solutions, emulsions, suspensions, etc.can be manufactured using diluents such as water, ethyl alcohol,macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylatedisostearyl alcohol and polyoxyethylene sorbitan fatty acid esters. Theyare preferably sterilized and rendered isotonic with respect to theblood. Sodium chloride, glucose or glycerin may be incorporated in thepharmaceutical compositions of the invention in an amount sufficient togive isotonic solutions. Solubilizers, buffers, analgesics and otheradditives in common use may also be added.

Further, coloring agents, preservatives, fragrants, flavors, sweetenersand other medicaments may be optionally incorporated in thepharmaceutical compositions of the invention.

The ointments in the form of pastes, creams, gels, etc. can bemanufactured using diluents such as white vaseline, paraffin, glycerin,cellulose derivatives, polyethylene glycol, silicone and bentonite.

The proportion of the compound of formula (1) as an active ingredient inthe pharmaceutical composition of the invention is not so critical butcan be selected from a broad range. Generally, it is preferable that theactive ingredient accounts for about 1 to 70 weight % of the finalcomposition.

There is no limitation on methods for administering the pharmaceuticalcompositions of the invention. The proper method can be determinedaccording to the dosage form, patient's age, sex, severity of diseaseand other conditions. For example, the tablets, pills, solutions,suspensions, emulsions, granules and capsules are orally administered.The injections are intravenously administered singly or in admixturewith a conventional replenisher such as glucose or amino acid, andoptionally administered singly by the intramuscular, intradermal,subcutaneous or intraperitoneal route. The suppositories areintrarectally administered.

The dosage of the pharmaceutical composition is suitably selectedaccording to the administration method, patient's age, sex or otherconditions, severity of disease, etc. The dosage of the activeingredient compound of the invention is preferably about 0.5-20 mg perkg body weight a day and this amount can be administered once or in 2-4divided doses a day.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is described below in more detail with referenceto Reference Examples and Examples. Reference Examples illustrateproduction processes for the starting compounds of the compounds of theinvention. Examples illustrate production processes for the compounds ofthe invention.

REFERENCE EXAMPLE 1

Preparation of 5-n-butyl-7-chloropyrazolo[1,5-a]pyrimidine

Step (1)

A suspension (120 ml) of 100 g of 3-aminopyrazole and 190 g of methyl3-oxoheptanoate in toluene was prepared and refluxed with heating at100° C. for 3 hours. After cooling, toluene was distilled off underreduced pressure and diethyl ether was added to the residue. Thecrystals precipitated were collected and washed with diethyl ether andthen with acetonitrile to provide 184 g of5-n-butyl-7-hydroxypyrazolo[1,5-a]pyrimidine as colorless crystals.

Step (2)

The crystals obtained in step (1), 40 g, were added to toluene toprepare 400 ml of a suspension. Thereto were added 80 ml of phosphorusoxychloride and 44 ml of triethylamine. The mixture was refluxed withheating for 4 hours. After completion of the reaction, the reactionmixture was concentrated under reduced pressure and the residue waspoured into ice water. The mixture was neutralized with sodium acetateand extracted with ethyl acetate. The organic layer was collected,washed with saturated aqueous sodium chloride solution, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (eluent:ethylacetate:n-hexane=1:9) to provide 41 g of the title compound as a lightyellow oily compound.

¹ H-NMR (δ:ppm) [CDCl₃ ] 0.96 (3H, t, J=7.3), 1.4-1.5 (2H, m), 1.7-1.8(2H, m), 2.83 (2H, t, J=7.8), 6.69 (1H, d, J=2.3), 6.86 (1H, s), 8.17(1H, d, J=2.3)

The following compounds were prepared in a similar manner as above.

(1) 5-(3-Butenyl)-7-chloropyrazolo[1,5-a]pyrimidine Oily compound

¹ H-NMR(δ: ppm) [CDCl₃ ] 2.5-2.6 (2H, m), 2.9-3.0 (2H, m), 5.0-5.1 (2H,m), 5.8-6.0 (1H, m), 6.70 (1H, d, J=2.5), 6.86 (1H, s), 8.18 (1H, d,J=2.5)

(2) 7-Chloro-5-ethoxymethylpyrazolo[1,5-a]pyrimidine Oily compound

¹ H-NMR(δ: ppm) [CDCl₃ ] 1.31 (3H, t, J=6.9), 3.65 (2H, q, J=6.9), 4.63(2H, s), 6.72 (1H, d, J=2.5), 7.22 (1H, s), 8.20 (1H, d, J=2.5)

(3) 7-Chloro-5-(2-furyl)pyrazolo[1,5-a]pyrimidine m.p.: 84-86° C.

(Recrystallization solvent: dichloromethane-n-hexane)

(4) 7-Chloro-5-(3-furyl)pyrazolo[1,5-a]pyrimidine m.p.: 143-145° C.

(Recrystallization solvent: dichloromethane-n-hexane)

(5) 7-Chloro-5-(2-thienyl)pyrazolo[1,5-a]pyrimidine m.p.: 120-122° C.

(Recrystallization solvent: dichloromethane-n-hexane)

(6) 7-Chloro-5-(3-thienyl)pyrazolo[1,5-a]pyrimidine m.p.: 123-125° C.

(Recrystallization solvent: dichloromethane-n-hexane)

(7) 7-Chloro-5-ethylthiomethylpyrazolo[1,5-a]pyrimidine Oily compound

¹ H-NMR(δ: ppm) [CDCl₃ ] 1.26 (3H, t, J=7.4), 2.5-2.6 (2H, q, J=7.4),3.82 (2H, s), 6.72 (1H, d, J=2.5), 7.14 (1H, s), 8.19 (1H, d, J=2.5)

REFERENCE EXAMPLE 2

Preparation of 7-chloro-5-(3-acetoxybutyl)pyrazolo[1,5-a]pyrimidine

Step (1)

Using 0.9 g of 3-aminopyrazole and 1.9 g of methyl2-methyl-β-oxo-1,3-dioxolane-2-valerate, the procedure of ReferenceExample 1 was followed. As a result, 1.85 g of7-hydroxy-5-[2-(2-methyl-1,3-dioxolan-2-yl)ethyl]pyrazolo[1,5-a]pyrimidinewas obtained as colorless crystals.

Step (2)

The compound obtained in step (1), 22 g, was dissolved in 500 ml ofacetic acid-water (4:1) and stirred at 50° C. for 3 days. Aftercompletion of the reaction, the reaction mixture was concentrated underreduced pressure and the remaining acetic acid-water was azeotropicallydistilled off with benzene. The residue was recrystallized fromethanol-n-hexane to provide 11 g of7-hydroxy-5-(3-oxobutyl)pyrazolo[1,5-a]pyrimidine as colorless crystals.

Step (3)

The compound obtained in step (2), 5.7 g, was dissolved in 120 ml ofmethanol. Sodium borohydride, 0.53 g, was added to the solution underice-cooling. The mixture was stirred at 0° C. for 2 hours. Aftercompletion of the reaction, the reaction mixture was acidified by addingdiluted hydrochloric acid dropwise and then extracted with chloroform.The organic layer was collected, washed with saturated aqueous sodiumchloride solution, dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The residue was recrystallized fromethanol-n-hexane to provide 4.16 g of7-hydroxy-5-(3-hydroxybutyl)pyrazolo[1,5-a]pyrimidine as colorlesscrystals.

Step (4)

The crystals obtained in step (3), 4.16 g, were dissolved in 40 ml ofacetic anhydride and 40 ml of pyridine and stirred at room temperaturefor 30 minutes. After completion of the reaction, the reaction mixturewas concentrated under reduced pressure and the residue wasrecrystallized from methanol-diethyl ether to provide 4.2 g of5-(3-acetoxybutyl)-7-hydroxypyrazolo[1,5-a]pyrimidine as colorlesscrystals.

Step (5)

The compound obtained in step (4) was treated in a similar manner as instep (2) of Reference Example 1. The title compound was obtained as alight yellow oily compound.

¹ H-NMR(δ: ppm) [CDCl₃ ] 1.30 (3H, t, J=6.4), 2.03 (3H, s), 2.0-2.1 (2H,m), 2.8-2.9 (2H, m),. 5.0-5.1 (1H, m), 6.70 (1H, d, J=2.0), 6.87 (1H,s), 8.18 (1H, d, J=2.0)

EXAMPLE 1

Preparation of5-(3-butenyl)-7-(4-pyridylmethoxy)-pyrazolo[1,5-a]pyrimidine

60% sodium hydride, 0.55 g, was added to a 10 ml-solution of 1.6 g of4-(hydroxymethyl)pyridine in DMF while being ice-cooled. After themixture was stirred at 0° C. for 30 minutes, a DMF solution (2.5 ml)containing 2.6 g of 5-(3-butenyl)-7-chloropyrazolo[1,5-a]pyrimidine wasadded dropwise while being ice-cooled. The mixture was stirred at thesame temperature for another 1 hour. After completion of the reaction,water was added to the reaction mixture. The crystals precipitated werecollected by filtration and washed with water and then with diethylether. The crude crystals obtained were recrystallized from ethylacetate-n-hexane to provide 1.5 g of the title compound as colorlesscrystals. The structure and melting point of the compound obtained areshown in Table 1.

In a similar manner as above in Example 1, the following compounds canbe prepared.

5-(3-Butenyl)-7-(3-pyridylmethoxy)pyrazolo[1,5-a]pyrimidine

5-(3-Butenyl)-7-(2-pyridylmethoxy)pyrazolo[1,5-a]pyrimidine

5-(3-Butenyl)-7-(5-methylpyrazin-2-ylmethoxy)-pyrazolo[1,5-a]pyrimidine

5-(3-Butenyl)-7-(3,4,5-trimethoxybenzyloxy)-pyrazolo[1,5-a]pyrimidine

5-(3-Butenyl)-7-benzyloxypyrazolo[1,5-a]pyrimidine

5-(3-Butenyl)-7-(4-methylphenoxy)pyrazolo[1,5-a]pyrimidine

5-(3-Butenyl)-7-phenoxypyrazolo[1,5-a]pyrimidine

5-(3-Butenyl)-7-(4-chlorophenoxy)pyrazolo[1,5-a]pyrimidine

5-(3-Butenyl)-7-(3-chlorophenoxy)pyrazolo[1,5-a]pyrimidine

5-(3-Butenyl)-7-(2-chlorophenoxy)pyrazolo[1,5-a]pyrimidine

5-(3-Butenyl)-7-(2,4-dichlorophenoxy)pyrazolo-[1,5-a]pyrimidine

5-(3-Butenyl)-7-(4-chlorobenzyloxy)pyrazolo[1,5-a]pyrimidine

5-(3-Butenyl)-7-(4-methoxybenzyloxy)pyrazolo[1,5-a]pyrimidine

5-(3-Butenyl)-7-(4,6-dimethylpyrimidin-2-yloxy)-pyrazolo[1,5-a]pyrimidine

5-(3-Acetoxybutyl)-7-(3-pyridylmethoxy)pyrazolo-[1,5-a]pyrimidine

5-(3-Acetoxybutyl)-7-(2-pyridylmethoxy)pyrazolo-[1,5-a]pyrimidine

5-(3-Acetoxybutyl)-7-(5-methylpyrazin-2-yl-methoxy)pyrazolo[1,5-a]pyrimidine

5-(3-Acetoxybutyl)-7-(3,4,5-trimethoxybenzyloxy)-pyrazolo[1,5-a]pyrimidine

5-(3-Acetoxybutyl)-7-benzyloxypyrazolo[1,5-a]pyrimidine

5-(3-Acetoxybutyl)-7-(4-methylphenoxy)pyrazolo-[1,5-a]pyrimidine

5-(3-Acetoxybutyl)-7-phenoxypyrazolo[1,5-a]pyrimidine

5-(3-Acetoxybutyl)-7-(4-chlorophenoxy)pyrazolo-[1,5-a]pyrimidine

5-(3-Acetoxybutyl)-7-(3-chlorophenoxy)pyrazolo-[1,5-a]pyrimidine

5-(3-Acetoxybutyl)-7-(2-chlorophenoxy)pyrazolo-[1,5-a]pyrimidine

5-(3-Acetoxybutyl)-7-(2,4-dichlorophenoxy)-pyrazolo[1,5-a]pyrimidine

5-(3-Acetoxybutyl)-7-(4-chlorobenzyloxy)pyrazolo-[1,5-a]pyrimidine

5-(3-Acetoxybutyl)-7-(4-methoxybenzyloxy)-pyrazolo[1,5-a]pyrimidine

5-(3-Acetoxybutyl)-7-(4,6-dimethylpyrimidin-2-yloxy)pyrazolo[1,5-a]pyrimidine

5-Ethoxymethyl-7-(3-pyridylmethoxy)pyrazolo[1,5-a]pyrimidine

5-Ethoxymethyl-7-(5-methylpyrazin-2-ylmethoxy)-pyrazolo[1,5-a]pyrimidine

5-Ethoxymethyl-7-(3,4,5-trimethoxybenzyloxy)-pyrazolo[1,5-a]pyrimidine

7-Benzyloxy-5-ethoxymethylpyrazolo[1,5-a]pyrimidine

5-Ethoxymethyl-7-(4-methylphenoxy)pyrazolo[1,5-a]pyrimidine

5-Ethoxymethyl-7-phenoxypyrazolo[1,5-a]pyrimidine

7-(4-Chlorophenoxy)-5-ethoxymethylpyrazolo[1,5-a]pyrimidine

7-(3-Chlorophenoxy)-5-ethoxymethylpyrazolo[1,5-a]pyrimidine

7-(2-Chlorophenoxy)-5-ethoxymethylpyrazolo[1,5-a]pyrimidine

7-(2,4-Dichlorophenoxy)-5-ethoxymethylpyrazolo-[1,5-a]pyrimidine a

7-(4-Chlorobenzyloxy)-5-ethoxymethylpyrazolo[1,5-a]pyrimidine

5-Ethoxymethyl)-7-(4-methoxybenzyloxy)pyrazolo-[1,5-a]pyrimidine

5-Ethoxymethyl)-7-(4,6-dimethylpyrimidin-2-yl-oxy)pyrazolo[1,5-a]pyrimidine

5-Ethylthiomethyl)-7-(3-pyridylmethoxy)pyrazolo-[1,5-a]pyrimidine

5-Ethylthiomethyl)-7-(2-pyridylmethoxy)pyrazolo-[1,5-a]pyrimidine

5-Ethylthiomethyl)-7-(5-methylpyrazin-2-yl-methoxy)pyrazolo[1,5-a]pyrimidine

5-Ethylthiomethyl)-7-(3,4,5-trimethoxybenzyloxy)-pyrazolo[1,5-a]pyrimidine

7-Benzyloxy-5-ethylthiomethylpyrazolo[1,5-a]pyrimidine

5-Ethylthiomethyl-7-(4-methylphenoxy)pyrazolo-[1,5-a]pyrimidine

5-Ethylthiomethyl-7-phenoxypyrazolo[1,5-a]pyrimidine

7-(4-Chlorophenoxy)-5-ethylthiomethylpyrazolo-[1,5-a]pyrimidine

7-(3-Chlorophenoxy)-5-ethylthiomethylpyrazolo-[1,5-a]pyrimidine

7-(2-Chlorophenoxy)-5-ethylthiomethylpyrazolo-pyrazolo[1,5-a]pyrimidine

7-(2,4-Dichlorophenoxy)-5-ethylthiomethyl-pyrazolo[1,5-a]pyrimidine

7-(4-Chlorobenzyloxy)-5-ethylthiomethylpyrazolo-[1,5-a]pyrimidine

5-Ethylthiomethyl-7-(4-methoxybenzyloxy)pyrazolo-[1,5-a]pyrimnidine

5-Ethylthiomethyl-7-(4,6-dimethylpyrimidin-2-yloxy)pyrazolo[1,5-a]pyrimidine

5-(2-Furyl)-7-(5-methylpyrazin-2-ylmethoxy)-pyrazolo[1,5-a]pyrimidine

5-(3-Furyl)-7-(5-methylpyrazin-2-ylmethoxy)-pyrazolo[1,5-a]pyrimidine

7-(5-Methylpyrazin-2-ylmethoxy)-5-(2-thienyl)-pyrazolo[1,5-a]pyrimidine

7-(5-Methylpyrazin-2-ylmethoxy)-5-(3-thienyl)-pyrazolo[1,5-a]pyrimidine

5-(2-Furyl)-7-(4,6-dimethylpyrimidin-2-yloxy)-pyrazolo[1,5-a]pyrimidine

5-(3-Furyl)-7-(4,6-dimethylpyrimidin-2-yloxy)-pyrazolo[1,5-a]pyrimidine

7-(4,6-Dimethylpyrimidin-2-yloxy)-5-(2-thienyl)-pyrazolo[1,5-a]pyrimidine

7-(4,6-Dimethylpyrimidin-2-yloxy)-5-(3-thienyl)-pyrazolo[1,5-a]pyrimidine

EXAMPLES 2-18

The compounds set forth in Table 1 were prepared in a similar manner asin Example 1. Table 1 shows the structure and melting points of thecompounds obtained.

EXAMPLE 19

Preparation of5-(3-hydroxybutyl)-7-(4-pyridylmethoxy)-pyrazolo[1,5-a]pyrimidine

The procedure of Example 1 was followed except using 340 mg of4-(hydroxymethyl)pyridine, 280 mg of5-(3-acetoxybutyl)-7-chloropyrazolo[1,5-a]pyrimidine and 105 mg of 60%sodium hydride and using DMF as a solvent. The title compound wasobtained as colorless crystals (50 mg). The structure and melting pointof the compound obtained are shown in Table 1.

The following compounds can be prepared in a similar manner as above inExample 19.

5-(3-Hydroxybutyl)-7-(3-pyridylmethoxy)pyrazolo-[1,5-a]pyrimidine

5-(3-Hydroxybutyl)-7-(2-pyridylmethoxy)pyrazolo-[1,5-a]pyrimidine

5-(3-Hydroxybutyl)-7-(5-methylpyrazin-2-yl-methoxy)pyrazolo[1,5-a]pyrimidine

5-(3-Hydroxybutyl)-7-(3,4,5-trimethoxybenzyloxy)-pyrazolo[1,5-a]pyrimidine

7-Benzyloxy-5-(3-hydroxybutyl)pyrazolo[1,5-a]pyrimidine

5-(3-Hydroxybutyl)-7-(4-methylphenoxy)pyrazolo-[1,5-a]pyrimidine

5-(3-Hydroxybutyl)-7-phenoxypyrazolo[1,5-a]pyrimidine

7-(4-Chlorophenoxy)-5-(3-hydroxybutyl)pyrazolo-[1,5-a]pyrimidine

7-(3-Chlorophenoxy)-5-(3-hydroxybutyl)pyrazolo-[1,5-a]pyrimidine

7-(2-Chlorophenoxy)-5-(3-hydroxybutyl)pyrazolo-[1,5-a]pyrimidine

7-(2,4-Dichlorophenoxy)-5-(3-hydroxybutyl)-pyrazolo[1,5-a]pyrimidine

7-(4-Chlorobenzyloxy)-5-(3-hydroxybutyl)pyrazolo-[1,5-a]pyrimidine

5-(3-Hydroxybutyl)-7-(4-methoxybenzyloxy)-pyrazolo[1,5-a]pyrimidine

5-(3-Hydroxybutyl)-7-(4,6-dimethylpyrimidin-2-yloxy)pyrazolo[1,5-a]pyrimidine

EXAMPLE 20

Preparation of4-[5-(3-butenyl)pyrazolo[1,5-a]pyrimidin-7-yloxymethyl]pyridine-1-oxide

5-(3-Butenyl)-7-(4-pyridylmethoxy)pyrazolo[1,5-a]pyrimidine (compound ofExample 1), 500 mg, was dissolved in dichloromethane to provide 5 ml ofa solution. Thereto was added 660 mg of 70% m-chloroperbenzoic acid. Themixture was stirred at 0° C. for 1 hour. After completion of thereaction, saturated aqueous sodium bicarbonate solution was added andthe mixture was extracted with chloroform. The organic layer wascollected, washed in sequence with water and saturated aqueous sodiumchloride solution, dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (eluent: chloroform:methanol=10:1) and recrystallizedfrom ethyl acetate-n-hexane to provide 110 mg of the title compound ascolorless crystals. The structure and melting point of the compoundobtained are shown in Table 1.

The following compounds can be prepared in a similar manner as above inExample 20.

4-[5-(3-Acetoxybutyl)pyrazolo[1,5-a]pyrimidin-7-yloxymethyl]pyridine-1-oxide

4-[5-(Ethoxymethyl)pyrazolo[1,5-a]pyrimidin-7-yloxymethyl]pyridine-1-oxide

2-[5-(Ethoxymethyl)pyrazolo[1,5-a]pyrimidin-7-yloxymethyl]pyridine-1-oxide

4-[5-(2-furyl)pyrazolo[1,5-a]pyrimidin-7-yloxymethyl]pyridine-1-oxide

3-[5-(2-furyl)pyrazolo[1,5-a]pyrimidin-7-yloxymethyl]pyridine-1-oxide

2-[5-(2-furyl)pyrazolo[1,5-a]pyrimidin-7-yloxymethyl]pyridine-1-oxide

4-[5-(3-furyl)pyrazolo[1,5-a]pyrimidin-7-yloxymethyl]pyridine-1-oxide

4-[5-(2-thienyl)pyrazolo[1,5-a]pyrimidin-7-yloxymethyl]pyridine-1-oxide

4-[5-(3-thienyl)pyrazolo[1,5-a]pyrimidin-7-yloxymethyl]pyridine-1-oxide

EXAMPLE 21

Preparation of3-bromo-5-(3-butenyl)-7-(4-pyridyl-methoxy)pyrazolo[1,5-a]pyrimidine

5-(3-Butenyl)-7-(4-pyridylmethoxy)pyrazolo[1,5-a]pyrimidine (compound ofExample 1), 500 mg, was dissolved in 10 ml of dimethoxyethane-water(3:1). The solution was cooled to 0° C. and 380 mg of NBS was added. Themixture was stirred at 0° C. for 1 hour and further stirred at roomtemperature for 1 hour. Water was added to the reaction mixture and thecrystals precipitated were collected by filtration. The crude crystalswere recrystallized from dichloromethane-n-hexane to provide 440 mg ofthe title compound as colorless crystals. The structure and meltingpoint of the compound obtained are shown in Table 1.

The following compounds can be prepared in a similar manner as above inExample 21.

5-(3-Acetoxybutyl)-3-bromo-7-(4-pyridylmethoxy)-pyrazolo[1,5-a]pyrimidine

3-Bromo-5-butyl-7-(5-methylpyrazin-2-ylmethoxy)-pyrazolo[1,5-a]pyrimidine

3-Bromo-5-ethoxymethyl-7-(4-pyridylmethoxy)-pyrazolo[1,5-a]pyrimidine

3-Bromo-5-ethoxymethyl-7-(2-pyridylmethoxy)-pyrazolo[1,5-a]pyrimidine

3-Bromo-5-(2-furyl)-7-(4-pyridylmethoxy)pyrazolo-[1,5-a]pyrimidine

3-Bromo-5-(2-furyl)-7-(3-pyridylmethoxy)pyrazolo-[1,5-a]pyrimidine

3-Bromo-5-(2-furyl)-7-(2-pyridylmethoxy)pyrazolo-[1,5-a]pyrimidine

3-Bromo-5-(2-furyl)-7-(3,4,5-trimethoxybenzyl-oxy)pyrazolo[1,5-a]pyrimidine

7-Benzyloxy-3-bromo-5-(2-furyl)pyrazolo[1,5-a]pyrimidine

3-Bromo-5-(2-furyl)-7-(4-methylphenoxy)pyrazolo-[1,5-a]pyrimidine

3-Bromo-5-(2-furyl)-7-phenoxypyrazolo[1,5-a]pyrimidine

3-Bromo-7-(4-chlorophenoxy)-5-(2-furyl)pyrazolo-[1,5-a]pyrimidine

3-Bromo-5-(3-furyl)-7-(4-pyridylmethoxy)pyrazolo-[1,5-a]pyrimidine

3-Bromo-7-(4-pyridylmethoxy)-5-(2-thienyl)-pyrazolo[1,5-a]pyrimidine

3-Bromo-7-(4-pyridylmethoxy)-5-(3-thienyl)-pyrazolo[1,5-a]pyrimidine

3-Bromo-7-(4-chlorobenzyloxy)-5-(2-furyl)-pyrazolo[1,5-a]pyrimidine

3-Bromo-7-(4-methoxybenzyloxy)-5-(2-furyl)-pyrazolo[1,5-a]pyrimidine

3-Bromo-5-(3-hydroxybutyl)-7-(4-pyridylmethoxy)-pyrazolo[1,5-a]pyrimidine

4-[3-bromo-5-(3-butenyl)pyrazolo[1,5-a]pyrimidin-7-yloxymethyl]pyridine-1-oxide

3-Bromo-5-(4-hydroxybutyl)-7-(4-pyridylmethoxy)-pyrazolo[1,5-a]pyrimidine

3-Bromo-7-(2-chlorophenoxy)-5-(2-furyl)pyrazolo-[1,5-a]pyrimidine

3-Bromo-7-(3-chlorophenoxy)-5-(2-furyl)pyrazolo-[1,5-a]pyrimidine

3-Bromo-7-(2,4-dichlorophenoxy)-5-(2-furyl)-pyrazolo[1,5-a]pyrimidine

3-Bromo-5-(2-furyl)-7-(4,6-dimethylpyrimidin-2-yloxy)pyrazolo[1,5-a]pyrimidine

3-Bromo-7-(4-chlorophenoxy)-5-(2-thienyl)-pyrazolo[1,5-a]pyrimidine

3-Bromo-5-ethylthiomethyl-7-(4-pyridylmethoxy)-pyrazolo[1,5-a]pyrimidine

EXAMPLE 22

Preparation of5-(4-hydroxybutyl)-7-(4-pyridylmethoxy)-pyrazolo[5-a]pyrimidine

5-(3-Butenyl)-7-(4-pyridylmethoxy)pyrazolo[1,5-a]pyrimidine (compound ofExample 1), 300 mg, was dissolved in 3.0 ml of anhydrous THF. Theretowere added dropwise 4.3 ml of a THF solution containing 0.5M of 9-BBN ina stream of argon at 0° C. The mixture was stirred at 0° C. for 1 hourand further stirred at room temperature for 1 hour. Thereto were added0.5 ml of water and 0.6 ml of aqueous 3M NaOH solution in sequence. Themixture was stirred at room temperature for 1 hour. Lastly 0.6 ml of 30%aqueous hydrogen peroxide solution was added and the mixture was stirredat room temperature for 1 hour. The reaction mixture was extracted withchloroform. The organic layer was collected, washed in sequence withwater and saturated aqueous sodium chloride solution, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (eluent:chloroform:methanol=20:1) and recrystallized from chloroform-ethylacetate to provide 70 mg of the title compound as colorless crystals.The structure and melting point of the compound obtained are shown inTable 1.

In a similar manner as above in Example 22, the following compounds canbe prepared using the compounds of the present invention wherein R¹ islower alkenyl (3-butenyl).

5-(4-hydroxybutyl)-7-(3-pyridylmethoxy)pyrazolo-[1,5-a]pyrimidine

5-(4-hydroxybutyl)-7-(2-pyridylmethoxy)pyrazolo-[1,5-a]pyrimidine

5-(4-hydroxybutyl)-7-(5-methylpyrazin-2-yl-methoxy)pyrazolo[1,5-a]pyrimidine

5-(4-hydroxybutyl)-7-(3,4,5-trimethoxybenzyloxy)pyrazolo[1,5-a]pyrimidine

7-benzyloxy-5-(4-hydroxybutyl)pyrazolo[1,5-a]pyrimidine

5-(4-hydroxybutyl)-7-(4-methylphenoxy)pyrazolo-[1,5-a]pyrimidine

5-(4-hydroxybutyl)-7-phenoxypyrazolo[1,5-a]pyrimidine

7-(4-chlorophenoxy)-5-(4-hydroxybutyl)pyrazolo-[1,5-a]pyrimidine

7-(3-chlorophenoxy)-5-(4-hydroxybutyl)pyrazolo-[1,5-a]pyrimidine

7-(2-chlorophenoxy)-5-(4-hydroxybutyl)pyrazolo-[1,5-a]pyrimidine

7-(2,4-dichlorophenoxy)-5-(4-hydroxybutyl)-pyrazolo[1,5-a]pyrimidine

7-(4-chlorobenzyloxy)-5-(4-hydroxybutyl)pyrazolo-[1,5-a]pyrimidine

5-(4-hydroxybutyl)-7-(4-methoxybenzyloxy)-pyrazolo[1,5-a]pyrimidine

5-(4-hydroxybutyl)-7-(4,6-dimethylpyrimidin-2-yloxy)pyrazolo[1,5-a]pyrimidine

EXAMPLES 23-28

The compounds set forth in Table 1 were prepared in a similar manner asin Example 1. Table 1 shows the structure and melting points of thecompounds obtained.

                                      TABLE 1                                     __________________________________________________________________________    1 #STR8##                                                                     Me: Methyl group, Et: Ethyl group, nBu: N-Butyl group,                        Ph: Phenyl group, Ac: Acetyl group                                            __________________________________________________________________________    Ex.                              Melting Point (° C.                   No. R.sup.1      R.sup.2  R.sup.3                                                                          A   (Recrystallization solvent)                  __________________________________________________________________________    1   CH.sub.2 ═CH--CH.sub.2 --CH.sub.2 --                                                   2 #STR9##                                                                              H  CH.sub.2                                                                          159˜161 (Ethyl acetate-n-hexane)           3 #STR10##                                                                                 2 #STR11##                                                                             H  CH.sub.2                                                                          113˜115 (Ethyl acetate-n-hexane)       3   nBu                                                                                        4 #STR12##                                                                             H  CH.sub.2                                                                          124˜126 (Dichloromethane-n-hexane)     4   EtOCH.sub.2 --                                                                             2 #STR13##                                                                             H  CH.sub.2                                                                          132˜134 (Dichloromethane-diethyl                                        ether)                                       5   EtOCH.sub.2 --                                                                             5 #STR14##                                                                             H  CH.sub.2                                                                          89˜92 (Dichloromethane-diethyl                                          ether)                                       6                                                                                 8 #STR15##                                                                                 2 #STR16##                                                                             H  CH.sub.2                                                                          169˜171 (Ethyl acetate-n-hexane)       7                                                                                 8 #STR17##                                                                                 5 #STR18##                                                                             H  CH.sub.2                                                                          164˜166 (Ethyl acetate-n-hexane)       8                                                                                 8 #STR19##                                                                                 6 #STR20##                                                                             H  CH.sub.2                                                                          156˜158 (Ethyl acetate-n-hexane)       9                                                                                 8 #STR21##                                                                                 7 #STR22##                                                                             H  CH.sub.2                                                                          136˜138 (Ethyl acetate-n-hexane)       10                                                                                8 #STR23##   Ph       H  CH.sub.2                                                                          174˜176 (Ethyl acetate-n-hexane)       11                                                                                8 #STR24##                                                                                 1 #STR25##                                                                             H  S.B.                                                                              157˜159 (Ethyl acetate-n-hexane)       12                                                                                8 #STR26##   Ph       H  S.B.                                                                              131˜133 (Ethyl acetate-n-hexane)       13                                                                                8 #STR27##                                                                                 2 #STR28##                                                                             H  S.B.                                                                              148˜150 (Ethyl acetate-n-hexane)       14                                                                                8 #STR29##                                                                                 2 #STR30##                                                                             H  CH.sub.2                                                                          180˜182 (Ethyl acetate-n-hexane)       15                                                                                9 #STR31##                                                                                 2 #STR32##                                                                             H  CH.sub.2                                                                          174˜176 (Ethyl acetate-n-hexane)       16                                                                                5 #STR33##                                                                                 2 #STR34##                                                                             H  CH.sub.2                                                                          160˜162 (Ethyl acetate-n-hexane)       17                                                                                8 #STR35##                                                                                 2 #STR36##                                                                             H  CH.sub.2                                                                          127˜129 (Ethyl acetate-n-hexane)       18                                                                                8 #STR37##                                                                                 3 #STR38##                                                                             H  CH.sub.2                                                                          124˜126 (Ethyl acetate-n-hexane)       19                                                                                0 #STR39##                                                                                 2 #STR40##                                                                             H  CH.sub.2                                                                          125˜127 (Ethyl acetate-n-hexane)       20  CH.sub.2 ═CH--CH.sub.2 --CH.sub.2 --                                                   4 #STR41##                                                                             H  CH.sub.2                                                                          129˜131 (Ethyl acetate-n-hexane)       21  CH.sub.2 ═CH--CH.sub.2 --CH.sub.2 --                                                   2 #STR42##                                                                             Br CH.sub.2                                                                          117˜119 (Dichloromethane-diethyl                                        eter                                         22  HO--CH.sub.2 CH.sub.2 --CH.sub.2 CH.sub.2 --                                               2 #STR43##                                                                             H  CH.sub.2                                                                          162˜164 (Chloroform-ethyl                                               acetate)                                     23                                                                                8 #STR44##                                                                                 6 #STR45##                                                                             H  S.B.                                                                              132˜134 (Diethyl ether-n-hexane)       24                                                                                8 #STR46##                                                                                 7 #STR47##                                                                             H  S.B.                                                                              112˜114 (Diethyl ether-n-hexane)       25                                                                                8 #STR48##                                                                                 8 #STR49##                                                                             H  S.B.                                                                              150˜152 (Diethyl ether-n-hexane)       26  nBu                                                                                        9 #STR50##                                                                             H  S.B.                                                                              68˜70 (n-Hexane)                       27                                                                                9 #STR51##                                                                                 0 #STR52##                                                                             H  S.B.                                                                              116˜118 (Diethyl ether-n-hexane)       28  EtSCH.sub.2 --                                                                             2 #STR53##                                                                             H  CH.sub.2                                                                          107˜109 (Ethyl acetate-n-hexane)       __________________________________________________________________________     *In column A. "SB" means "Single bond".                                  

Pharmacological Test Example 1

Using 6-week-old male Wistar rats (n=7/group), the pain threshold ofeach rat's left hind paw was determined using Analgesy-Meter (Unicom) inaccordance with the Randall-Selitto method [Randall, L. O. and Selitto,J. J., Arch. Int. Pharmacodyn., 111, 409 (1957)]. The value thusobtained was termed "pre-value".

One hour after measurement of the pre-value, 0.1 ml of a 20% yeastsuspension was subcutaneously injected into the left hind paw of eachrat. Immediately after the yeast injection, a 5% gum arabic suspensioncontaining the compound of the invention was orally administered to therats of the test group in an amount of 10 ml/kg, whereas a 5% gum arabicsuspension (not containing the compound of the invention) wasadministered likewise to the rats of the control group.

The pain threshold of each rats left hind paw was determined in the samemanner as above at an interval of exactly one hour from the time of theyeast injection. The value thus obtained was termed "Post-value".

The recovery (%) of the pain threshold was calculated from post-valuesand pre-values of the rats in each group, by means of the followingformula.

Recovery of pain threshold (%)= ##EQU1##

The results (the highest recovery %) are shown in Table 2.

                  TABLE 2                                                         ______________________________________                                        Example   Recovery Dosage    Time from yeast injection                        No.       (%)      (mg/kg)   (hr. later)                                      ______________________________________                                        1         65.3     10        4                                                4         69.3     3         1                                                9         75.4     3         3                                                13        102.9    3         4                                                19        47.9     1         3                                                ______________________________________                                    

Pharmacological Test Example 2

Using 6-week-old male Wistar rats (n=7/group), the pain threshold ofeach rat's left hind paw was determined using Analgesy-Meter (Unicom) inaccordance with the Randall-Selitto method [Randall, L. O. and SelittoJ. J., Arch. Int. Pharmacodyn., 111, 409 (1957)]. The value thusobtained was termed "pre-value".

One hour after measurement of the pre-value, a 5% gum arabic suspensioncontaining the compound of the invention was orally administered to therats of the test group in an amount of 10 ml/kg so that the dosage ofthe compound of the invention was 1 mg/kg, whereas a 5% gum arabicsuspension (not containing the compound of the invention) wasadministered likewise to the rats of the control group. One hour later,an aqueous physiological saline solution containing substance P (25ng/0.1 ml) was subcutaneously injected into the left hind paw of eachrat.

The pain threshold of each rat's left hind paw was determined in thesame manner as above at a predetermined interval from the time of thesubstance P injection. The value thus obtained was termed "post-value".

The recovery (%) of the pain threshold was calculated from post-valuesand pre-values of the rats in each group, by means of the followingformula. ##EQU2##

The results (the highest recovery %) are shown in Table 3.

                  TABLE 3                                                         ______________________________________                                                     Recovery Time from substance P                                   Example No.  (%)      injection (minutes later)                               ______________________________________                                         1           118.6    30                                                       4           100.7    15                                                       5           73.4     60                                                       6           52.0     60                                                       9           60.3     60                                                      13           63.6     60                                                      14           56.2     60                                                      16           56.8     30                                                      18           33.1     30                                                      20           89.2     60                                                      22           45.4     60                                                      23           34.9     30                                                      25           52.3     60                                                      26           43.5     60                                                      28           52.9     30                                                      ______________________________________                                    

Given below are Formulation Examples for manufacturing analgesiccompositions of the invention.

Formulation Example 1

Manufacture of tablets

Tablets (1000 tables) for oral administration, each containing 5 mg ofthe compound obtained in Example 1, were manufactured according to thefollowing formula:

    ______________________________________                                        Compound of Example 1     5     g                                             Lactose (Japanese pharmacopoeia: JP)                                                                    50    g                                             Corn starch (JP)          25    g                                             Crystalline cellulose (JP)                                                                              25    g                                             Methyl cellulose (JP)     1.5   g                                             Magnesium stearate (JP)   1     g                                             ______________________________________                                    

More specifically, the compound of Example 1, lactose, corn starch andcrystalline cellulose were fully blended and granulated using a 5%aqueous methyl cellulose solution. The granulated mixture was passedthrough a 200-mesh sieve and dried carefully. The dried granules werepassed through a 200-mesh sieve, and the granules under the sieve weremixed with magnesium stearate and compression-molded into tablets.

Formulation Example 2

Manufacture of capsules

Two-piece hard gelatin capsules (1000 units) for oral administration,each containing 10 mg of the compound obtained in Example 9, weremanufactured according to the following formula:

    ______________________________________                                        Compound of Example 9   10    g                                               Lactose (JP)            80    g                                               Corn starch (JP)        30    g                                               Talc (JP)               5     g                                               Magnesium stearate (JP) 1     g                                               ______________________________________                                    

More specifically, the above ingredients were finely pulverized andblended to give a homogeneous composition. This composition was filledinto propersized capsule shells for oral administration.

Industrial Applicability

The pyrazolo[1,5-a]pyrimidine derivatives according to the presentinvention have potent analgesic effects and are useful as analgesics.

What is claimed is:
 1. A pyrazolo[1,5-a]pyrimidine derivative of theformula ##STR54## wherein R¹ is lower alkenyl, hydroxy(lower)alkyl,(lower)alkanoyloxy(lower)alkyl, (lower)alkoxy(lower)alkyl,(lower)alkylthio(lower)alkyl, furyl or thienyl, R² is pyridyl,1-oxide-pyridyl, lower alkyl-substituted pyrazinyl, loweralkyl-substituted pyrimidinyl, or phenyl which may have 1 to 3substituents selected from the group consisting of lower alkyl, loweralkoxy and halogen, R³ is hydrogen or halogen, and A is a single bond orlower alkylene.
 2. A pyrazolo[1,5-a]pyrimidine derivative according toclaim 1, which is selected from the group consisting of the compounds offormula (1) wherein R¹ is furyl and R² is phenyl which may have 1 to 3substituents selected from the group consisting of lower alkyl, loweralkoxy and halogen, and those wherein R² is pyridyl or 1-oxide-pyridyland A is lower alkylene.
 3. A pyrazolo[1,5-a]pyrimidine derivativeaccording to claim 2, which is selected from the group consisting of thecompounds wherein R¹ is lower alkenyl, R² is pyridyl or 1-oxide-pyridyl,R³ is hydrogen and A is lower alkylene and the compounds wherein R¹ isfuryl and R² is phenyl which may have 1 to 3 lower alkoxy groups, R³ ishydrogen and A is lower alkylene.
 4. A pyrazolo[1,5-a]pyrimidinederivative according to claim 3 wherein R¹ is 3-butenyl or 2-furyl and Ais methylene.
 5. A pyrazolo[1,5-a]pyrimidine derivative according toclaim 4, which is selected from the group consisting of5-(3-butenyl)-7-(4-pyridylmethoxy)pyrazolo[1,5-a]pyrimidine,4-[5-(3-butenyl)pyrazolo[1,5-a]pyrimidin-7-yloxymethyl]pyridine-1-oxideand 5-(2-furyl)-7-(3,4,5-trimethoxybenzyloxy)pyrazolo[1,5-a]pyrimidine.6. An analgesic composition which comprises an effective amount of apyrazolo[1,5-a]pyrimidine derivative defined in one of claims 1-5 and apharmaceutically acceptable carrier.
 7. A method for relieving pain,which comprises administering to a patient an effective amount of apyrazolo[1,5-a]pyrimidine derivative of the formula ##STR55## wherein R¹is lower alkenyl, hydroxy(lower)alkyl, (lower)alkanoyloxy(lower)alkyl,(lower)alkoxy(lower)alkyl, (lower)alkylthio(lower)alkyl, furyl orthienyl, R² is pyridyl, 1-oxide-pyridyl, lower alkyl-substitutedpyrazinyl, lower alkyl-substituted pyrimidinyl, or phenyl which may have1 to 3 substituents selected from the group consisting of lower alkyl,lower alkoxy and halogen, R³ is hydrogen or halogen, and A is a singlebond or lower alkylene.
 8. The method according to claim 7, wherein thepyrazolo[1,5-a]pyrimidine derivative is selected from the groupconsisting of the compounds of formula (1) wherein(a) R¹ is furyl and R²is phenyl optionally having 1 to 3 substituents selected from the groupconsisting of lower alkyl, lower alkoxy and halogen, and (b) R² ispyridyl or 1-oxide-pyridyl and A is lower alkylene.
 9. The methodaccording to claim 7, wherein the pyrazolo[1,5-a]pyrimidine derivativeis selected from the group consisting of the compounds of formula (1)wherein(a) R¹ is lower alkenyl, R² is pyridyl or 1-oxide-pyridyl, R³ ishydrogen and A is lower alkenylene and (b) R¹ is furyl and R² is phenyloptionally having 1 to 3 lower alkoxy groups, R³ is hydrogen and A islower alkylene.
 10. The method according to claim 7, wherein R¹ is3-butenyl or 2-furyl and A is methylene.
 11. The method according toclaim 7, wherein the pyrazolo[1,5-a]pyrimidine derivative is selectedfrom the group consisting of5-(3-butenyl)-7-(4-pyridylmethoxy)pyrazolo[1,5-a]pyrimidine,4-[5-(3-butenyl)pyrazolo[1,5-a]pyrimidin-7-yloxymethyl]pyridine-1-oxideand 5-(2-furyl)-7-(3,4,5-trimethoxy-benzyloxy)pyrazolo[1,5-a]pyrimidine.12. The method according to claim 7, wherein the method of administeringthe pyrazolo[1,5-a]pyrimidine derivative to said patient is oral,intravenous, intramuscular, intradermal, subcutaneous, intra-peritoneal,or intrarectal administering.
 13. A pharmaceutical composition suitablefor use as a pain reliever comprising the pyrazolo[1,5-a]pyrimidinederivative of claim 1 and at least one pharmaceutically acceptablecarrier.
 14. The pharmaceutical composition according to claim 13,wherein the composition is in a dosage form selected from the groupconsisting of tablets, pills, powders, solutions, suspensions,emulsions, granules, capsules, suppositories, injections and ointments.15. A unit dose of the pyrazolo[1,5-a]pyrimidine derivative of claim 1,wherein the unit dose is about 0.125-20 mg per kg body weight of apatient to whom the dose is administered.